Major depressive disorder (MDD) is highly prevalent and impactful, with active symptoms present in 4% of the adult population (1). Although MDD exhibits multiple molecular phenotypes (2-5) there is accumulating evidence for a role of inflammation in generating symptoms of a major depressive episode (MDE). For example, induction of inflammation is associated with sad mood in humans (6) and direct induction of the central immune system in rodents is associated with the sickness syndrome of anhedonia, weight loss and anorexia which overlap with the diagnostic criteria for MDE (7). Also in MDD, several markers of peripheral inflammation, including C-reactive protein, IL-6 and TNF-α are frequently increased (8). Interestingly, conditions which create neuroinflammation such as traumatic brain injury, systemic lupus erythematosus and multiple sclerosis are associated with prevalence rates of MDE as high as 50% suggesting a link between brain inflammation and mood symptoms (9).
Obsessive compulsive disorder (OCD) is another prevalent disorder which affects many. OCD is an example of a neuropsychiatric disorder which may be associated with, or diagnosed along with, MDD. The exact cause of OCD remains unclear, and diagnosis is most often based on the symptoms experienced and the severity thereof.
Presently, it is not clear whether brain inflammation occurs during a current major depressive episode (MDE) because most postmortem investigations of neuroinflammation sampled either MDD with a history of MDE or suicide victims with varied diagnoses. Within such studies, the samples of subjects with current MDE were small. Van Otterloo et al., (10) reported no difference in density of activated microglia, in the white matter of the orbitofrontal region in 10 MDD subjects. Dean et al. sampled 10 MDD subjects and found significantly increased levels of the transmembrane form of TNF in the dorsolateral prefrontal cortex but no difference in levels of this form of TNF in the anterior cingulate cortex and no difference in the soluble form of TNF in either region (11). Steiner et al. reported increased density of quinolinic acid positive cells, a marker influenced by microglial activation, in the anterior cingulate cortex of 7 MDE subjects (12). Microarray studies have had mixed results, with a positive finding by Shelton et al. of increased pro- and anti-inflammatory cytokine mRNA in Brodmann Area 10 (BA10) in 14 MDD subjects (13) but several other microarray studies, most of which sampled adjacent regions of the prefrontal cortex, did not identify this result (14, 15) Amongst investigations in suicide victims one study reported greater HLA-DR staining, a marker of microglial activation, in the dorsolateral prefrontal and anterior cingulate cortex (16) and a second study reported greater levels of IL-6, TNF-α, and IL-1β in BA10 (17). Neither study of suicide found a relationship to MDD (or MDE) but there were less than 10 subjects with MDD in each study. The mixed results among postmortem investigations in MDD have been attributed to issues of variation in brain regions sampled, inclusion of early and late onset MDD, comorbidity of other psychiatric disorders and addiction and, with the exception of the microarray studies, small sample size, although it is plausible that lack of focus on sampling the state of MDE may be important for investigations of neuroinflammation. Torres-Platas reported an increased ratio of primed relative to ramified microglia in the white matter of the dorsal anterior cingulated white matter in a sample of 24 depressed suicide victims compared to 17 healthy controls, however, this was one of three ratios evaluated so it is unclear whether this result would be statistically meaningful if corrected for by the number of comparisons completed.
To determine whether neuroinflammation occurs in MDE secondary to MDD, positron emission tomography may be applied to measure translocator protein (TSPO) binding in vivo. TSPO is an 18 kDa protein located on outer mitochondrial membranes in microglia and increased expression of TSPO occurs when microglia are activated during neuroinflammation (18). Recently, a new generation of positron emission tomography (PET) radiotracers were developed with superior quantification of TSPO binding and among these, [18F]FEPPA has excellent properties including high, selective affinity for TSPO (19), increased binding during induced neuroinflammation (20) and a high ratio of specific binding relative to free and non-specific binding (21).
To date, one neuroimaging study applied [11C]PBR28 PET to investigate TSPO levels in MDD, which was negative (22). This earlier study assessed whether TSPO levels were elevated in a sample of 10 MDD subjects (scanned once) under a variety of states (treated, untreated, symptomatic, partially symptomatic) hence, this study cannot be considered definitive for determining whether TSPO binding is elevated in MDE. Scores on the Montgomery-Asberg Depression Rating Scale on the PET scan day ranged from 5 to 30, indicating that the severity ranged from almost asymptomatic to moderately symptomatic. Other issues which limit interpretation of this study include potential bias of ongoing antidepressant use, heterogeneity of combined sampling of early and late onset MDD, and incomplete information regarding a TSPO polymorphism (rs6971) known to influence binding of the new generation of TSPO PET radioligands, including [11C]PBR28 and [18F]FEPPA (23, 24).
Since imaging the brain during a MDE is costly, technically challenging and impractical in a clinical setting, peripheral markers correlating to brain inflammation, depression, MDE, MDD, and/or other neuropsychiatric disorders such as, for example, OCD, are needed. Further, there is also a need in the art for peripheral measures correlating to microglia activation in a subject.